Abstract The last two decades mark a conceptual revolution in immune recognition, switching from one based on engagement of clonal receptor to one that integrates pattern recognition with clonal recognition. The pathogen-associated molecular patterns (PAMP) interacts with several evolutionally conserved pathways, such as Toll-like receptors (TLR) or NOD-like receptors (NLR) to initiate adaptive immune response, although it is now clear that the function of this pattern recognition goes well beyond innate immune protection and initiation of adaptive immunity. In addition to foreign pathogens, the host is also able to respond to injuries through inflammation. Interestingly, one of the signature molecules released during cellular injury, HMGB1, also interacts with TLR. However, this response must be kept under control in order to avoid excessive autoimmune damage following tissue injuries. How the engagement of the same receptor by PAMP would lead to different outcomes than elicited by molecules released during cellular injury remains largely unknown. In the last funding period, we discovered that CD24 on APC negatively regulates T-cell responses to homeostatic cue. In search for molecular mechanisms by which CD24 negatively regulate APC function, we identified two novel CD24 ligands, HMGB1 and SIglec G/10. Based on these discoveries, we hypothesize that CD24 may serve as an important negative regulator for the host response to cellular injury and a molecular mechanism for the negative regulation. This hypothesis will be tested in three sets of experiments. 1). What is the role for CD24-HMGB1 interaction in limiting inflammation, homeostatic proliferation and potential priming of T cells by contents of cellular injuries? We will first study the response of WT and CD24-deficient neonates for their inflammatory response and homeostatic proliferation to HMGB1 stimulation. This will be extended into adult immune competent mice to determine whether CD24 prevent priming of autoreactive T cells specific for antigens released in the context of cellular injury. 2). What is the role for SIglecG/10 in the enhanced homeostatic proliferation? Our preliminary studies indicated that CD24 physically interacts with SIglec 10/G. We will examine the role for SIglecG/10 in APC and T cells in their responses to HMGB1 and determine whether the effect of target mutation with SIglecG and CD24 are interchangeable or synergistic in regulating inflammatory response. 3). What is the molecular mechanism by which CD24 down-regulates inflammatory response initiated by HMGB1? Since SIglecG/10 has ITIM motifs in the cytoplasmic domain that was known to be associated with SHP1 and SHP2, we will test a hypothesis that SIglecG/10 is the signal transducer for CD24-mediated negative regulation. Our proposed studies may reveal a novel pathway for the regulation of host response to cellular injury. Since CD24 defects block the development of autoimmune diseases, our study provides a molecular basis linking inflammation to immunity to cancer or infection without provoking autoimmune diseases.